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Welcome to Northeastern University’s science and research blog. We call it iNSolution because that’s what our faculty and student researchers are in the business of—finding solutions to societal problems while simultaneously contributing to the fundamental knowledge base of their respective fields.

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A new age for drug discovery

In the last fifty years, phar­ma­ceu­tical com­pa­nies have spent tens of bil­lions of dol­lars trying to find new classes of antibi­otic drugs. Only one has made it into clin­ical prac­tice. Seem sur­prising to you? Yeah, me too.

At the same time, antibac­te­rial resis­tance has been rising, meaning the pathogens that infect us are get­ting better and better at staying alive. If we con­tinue like this, said biology pro­fessor Kim Lewis, “we’ll go back to the age of epi­demics and pandemics…society is at risk.”

The stan­dard approach for facil­i­tating drug dis­covery has been to pump more money into the system. “But this is not about a lack of money,” Lewis said. “It’s the paucity of ideas, not money, that did in this field.”

In today’s issue of Nature mag­a­zine Lewis’ essay “Recover the lost art of drug dis­covery” lays out a clear roadmap for what went wrong in the field, what worked and where we should go from here.

During the “golden age” of antibi­otic dis­covery in the 1940s, the pri­mary approach, invented by Selman Waksman, was to screen soil microbes for their ability to pro­duce nat­ural antibi­otics. Large phar­ma­ceu­tical com­pa­nies got rich with this method, Lewis said. But over time the approach col­lapsed: the same com­pounds emerged over and over again. As it turned out, only tiny frac­tion of all bac­teria could be cul­ti­vated in the lab.

In a 2002 article in Sci­ence, Lewis and pro­fessor Slava Epstein pre­sented a novel strategy for cul­ti­vating pre­vi­ously uncul­ti­vated bac­teria. “The idea was to grow bac­teria in their nat­ural envi­ron­ment,” Lewis explained. This strategy opened the door for revi­tal­izing the Waksman plat­form, which had pre­vi­ously been use­less for 99 per­cent of bac­teria, the so-​​called “uncul­tivable” bac­teria. Their teams at NU are now col­lab­o­rating with Novo­Bi­otic, a Biotech startup in Cam­bridge, MA, that licensed this inven­tion, to dis­cover novel antibi­otics from pre­vi­ously uncul­tured bacteria.

The 1940s and 50s also saw the heyday for syn­thetic antibi­otic dis­covery. “When the Waksman plat­form col­lapsed, the industry came up with two new log­ical approaches,” Lewis said. First was rational design, in which syn­thetic chemists cre­ated new com­pounds that specif­i­cally tar­geted the pro­teins inside pathogens based on their mol­e­c­ular struc­tures. These failed, how­ever, because they were inca­pable of pen­e­trating the com­plex bac­te­rial cell envelope.

The second approach was high-​​throughput screening, which tests thou­sands of syn­thetic com­pounds in par­allel for their tar­geting abil­i­ties. Again, the dif­fi­culty of pen­e­tra­tion pre­vented this oth­er­wise extremely suc­cessful method from gaining trac­tion in the antibi­otic dis­covery field, said Lewis.

In his essay, Lewis pro­poses to estab­lish a set of “rules for pen­e­tra­tion.” He sug­gests char­ac­ter­izing 100 or so com­pounds that are capable of pen­e­trating the bac­te­rial enve­lope (regard­less of antibi­otic activity) and teasing out the common prop­er­ties that seem to be impor­tant for pen­e­tra­tion. “We can then build a library of com­pounds which takes these new rules into account,” he said. “Then, if you are ratio­nally designing an inhibitor you can also put into it prop­er­ties that you know are essen­tial for penetration.”

In the first sen­tence of the essay, Lewis says “the more we know about antibi­otics, the fewer we can dis­cover.” The problem, he explained, is that every time the industry has tried to improve, it has done so based on imper­fect knowl­edge. Lewis believes we have finally come full circle, and are now in a posi­tion to revi­talize the lost art of drug dis­covery. He is working on a second article geared toward fellow micro­bi­ol­o­gists that will out­line the sci­en­tific require­ments to make his vision a reality.

About the Writer

Angela Herring is the science writer for the Northeastern news team. In a past life, she made fullerenes (aka bucky balls) at a small chemical company outside of Boston while freelance writing for the Harvard Stem Cell Institute, the Broad Institute and Novartis Biomedical Research Institutes. She earned her Bachelor's degree in chemistry and literature from Bennington College in 2005. In addition to writing stories for the News@Northeastern, she also maintains the university's research blog: iNSolution.

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